A major treatment modality in the advanced disease setting is chemotherapy, with cisplatin-based regimens playing significant roles in the cancer management strategy of a number of cancers, including ovarian cancer, mesothelioma and non-small cell lung cancer. However, the majority of advanced cancer cases relapse and fail therapy due to the onset of cisplatin resistance, and patients eventually succumb to their disease. The most recent advance about two decades ago was the inclusion of taxol to the platinum regimen, but this has only provided short-term incremental benefit without impacting the 5-year survival rate. Thus, cisplatin resistance is a significant drawback, and there is a desperate need to understand the causes of resistance, so new agents can be developed. A major understanding emerging from our work is that wild-type p53 features prominently in the resistance phenotype and this represents a major puzzle why the apoptotic function of p53 is being inhibited. Since many advanced and refractory cancer disease types include substantial numbers of tumors that harbor wild-type p53, there is reason to believe that a common defect in a key gene or pathway may be the cause of p53 failing to become functionally activated. Based on the strong relationship of mutual exclusivity, tumors with wild-type p53 are likely to have defective Chk2 expression, and this defect will impact post-translational modification of p53 that is essential for stabilization and stimulation of its function. Indeed, wild-type p53 in cisplatin-resistant tumor cells often demonstrates defective function. Since specific cancers have intrinsic affinity for platinum drugs, we hypothesize that defective Chk2 expression prevents stabilization and/or stimulation of wild-type p53 in cisplatin-resistant cancers, and that platinum analogs can be designed to activate an alternative kinase to maximally restore p53 inducibility and cytotoxic activity. We will address this hypothesis through three specific aims: 1) Characterize cisplatin resistance as related to defective Chk2 in tumor panels harboring wild-type p53;2) Identify the kinase activated by platinum analogs that restores p53 function in cisplatin-resistant cells;and 3) Establish structure-activity relationships for lead optimization and identify an analog that maximally stabilizes and stimulates wild-type p53 in resistant Chk2-defective tumor cells. Based on mouse models, activation of wild-type p53 is sufficient to kill tumor cells, and this raises the potential that targeting cisplatin resistance through a mechanism-directed drug development approach will restore wild-type p53 function and significantly increase response and 5-yr survival rates. PUBLIC HEALTH RELEVANCE: Advanced solid cancers are treated with cisplatin-based regimens, but the response is not durable and up to 90% of the patients may die as the tumor demonstrates resistance to therapy. Cancers that still harbor the normally-apoptotic wild-type p53 gene are the most resistant, and we will investigate why p53 is not functioning to allow rational therapies to emerge. Our mechanism-based strategy will identify drugs that will have potential for curative therapies to be realized.